The present invention relates to plant-derived chemotherapeutic compounds. More particularly, the invention is directed to 9-dihydro-13-acetylbaccatin III, a natural product isolated from Taxus canadensis, as well as novel analogs of taxol prepared therefrom.
Taxol, a member of the taxane family of terpenes, is of interest as a chemotherapeutic agent against a broad range of cancers. Taxol has been shown to be effective against advanced breast and ovarian cancers in clinical trials, and has exhibited promising activity against a number of other tumor types in preliminary investigations. A summary of the current state of taxol research, development and clinical testing may be found in Borman, Chemical & Engineering News (Sep. 2, 1991), 11-18; a review of synthetic efforts in the taxol field is provided by D. G. I. Kingston in Pharmacol. Therap. (1992), in press.
Taxol, which possesses the structural formula ##STR2## is currently limited in supply, as it is obtained by extraction primarily from the bark and, to a lesser amount, the leaves of trees and bushes of the genus Taxus. The primary source of taxol, the Pacific yew Taxus brevifolia, is a slow-growing evergreen with limited geographic distribution and increasing scarcity. Furthermore, the isolation of taxol, which constitutes less than 400 parts per million of the tree bark, is a difficult, low-yield and expensive process. Neither long-term nor large-scale harvesting of yews is considered an acceptable option for ecological as well as commercial reasons. There is, consequently, a pressing need for additional supplies of taxol for clinical use and testing.
While the needles of other Taxus species are being explored as renewable sources of taxol and its precursors, other researchers have attempted to produce taxol in tissue and cell culture. Total chemical synthesis of the compound and its related analogs has been attempted but not yet been achieved. The chemical conversion of naturally occurring taxol precursors such as baccatin III and cephalomannine to taxol itself or its analogs has been reported; however, additional routes for production of potentially active taxols and related compounds are still needed.
Taxol prodrugs or derivatives having greater water solubility than the naturally-occurring taxols have also been sought. In the search for new derivatives with potentially enhanced solubility, one of the sites on the molecule where attention has been directed is the ketone function at the C-9 position. Taxol is very resistant to reduction, and the C-9 carbonyl group is specifically resistant to reduction, even with various hydride reagents. Few compounds having anything other than a carbonyl group at C-9 have been disclosed. In U.S. Pat. Nos. 5,015,744 and 4,876,399, issued to Holton et al., taxol derivatives acetylated at the C-7, C-9 and C-10 positions are generically disclosed. The '744 patent does not, however, provide means for preparing the C-9 alkanoyloxy derivatives. The '399 patent contains illustrations of 7-deoxy compounds possessing both C-9 and C-10 O-acetyl groups. These compounds are taxol analogs that presumably may be synthesized via a taxusin synthesis, in which the vicinal hydroxyl groups are protected during the synthetic procedure with an acetonide group. There is no suggestion, however, that the free C-7, C-9 diol could be produced. Further, no scheme is proposed that would allow synthesis of analogs of taxol that possess a free hydroxyl group at C-9. Thus, the 9-dihydro derivatives of taxol and baccatin III have not been obtained as synthetic products, and 9-dihydro compounds in the taxol and baccatin series have not previously been isolated from natural sources.
The ability to synthesize 9-dihydrotaxol compounds having potentially superior pharmacologic properties may offer significant advantages to the chemist and pharmacologist. It is expected that a 9-dihydro derivative would have improved water solubility. Further, the 9-hydroxyl group of such a derivative would provide an additional functionality for further derivatization or prodrug preparation. In addition, the presence of a hydroxyl group instead of a carbonyl function at this position would impart greater stability to the molecule in that epimerization at position C-7, which has been shown to reduce the activity of the compound, would no longer be facile.